Roya Zandi, a professor at University of California, Riverside, and her former graduate student, Siyu Li, have successfully modeled the formation of the virus that spreads COVID-19 for the first time. On September 20 of this year, Dr. Zandi, a professor of the physics and astronomy department, and Li, a postdoctoral researcher at Songshan Lake Materials Laboratory in China, published a paper in Viruses. It is a peer-reviewed journal of virology detailing the formation and assembly of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The simulations in the study reveals new information about the viral life and could aid in future drug development.

The sheer number of viruses in the coronavirus family means that a massive effort is needed for scientists around the world to better understand them. SARS-CoV-2 is “a large positive-stranded RNA genome” made of about 30,000 nucleotides and 10,000 amino acids within N proteins and is “further encapsulated by an envelope” which protects its genetic material. During the maturation stage known as “budding,” the virus acquires the envelope from the host cell. During budding, the virus curves and completes its formation. The M protein “provides a scaffold” for the budding and works with the E protein to produce virions. The S protein surrounds the coronavirus like a crown and facilitates the virus’s entrance to the cellular membrane of the host cell. Their models investigate the self assembly of the four structural proteins, Envelope (E), Membrane (M), Nucleocapsid (N), and Spike (S).

Most of the formation and assembly processes of coronaviruses are elusive as they occur over nanoseconds and cannot be holistically analyzed by all-atom molecular dynamics simulations that examine molecules at the atomic level. To combat these difficulties, they designed coarse-grained (CG) models for the proteins, RNA, and phospholipid membrane. A CG model is used to simplify complicated systems while “keeping the main chemical/physical peculiarities” and to “extend time and length scales” of the systems. In the model, a protein is considered a “large entity” which is represented by a “bead.”

Previous vaccines targeted the S protein to prevent the virus from attaching and entering the host cell, however, a mutation in the S protein can easily decrease the effectiveness of the vaccine. Using simulations, they found that the N protein plays a crucial role in the packaging and condensing of the viral ribonucleic acid (RNA) in its genome. Coronavirus has “the largest genome … among all RNA viruses,” which means that the oligomerization of the N protein is especially important in viral assembly. They found that without oligomerization – a process that stabilizes the protein and “allows it to form large structures”– the viral RNA will not be able to be packaged.

The study also revealed that the “intrinsic curvature of the M protein” is integral to viral budding and that “under no circumstances were [they] able to observe the… budding [with] the absence of the M protein.” They noted that even though the M protein is the most prevalent in the virus, yet limited by “resolution in electron microscopy imaging,” knowledge on all structural proteins “[remain] rudimentary.” Li explains that, “The experimental studies regarding the specific role of each of the several structural proteins… are soaring but many details remain unclear.”

Everything considered, Zandi believes this study has the potential to “inform the design of effective antiviral drugs” to halt viral replication via dismantling factors in the viral assembly stage. It could also be of interest for future scientists looking to apply “physics-based methods” to study viral formation.

“Understanding viral assembly has always been a key step leading to therapeutic strategies,” Zandi said. She explains that “simulations of viruses… have had a remarkable impact on elucidating their assembly and providing means to combat them.” She admits that “even the simplest questions regarding the formation of SARS-CoV-2 remain unanswered.”

More information can be found in Li and Zandi’s paper.